Genetic Variant BUD13:p.Phe576Leu (chr11-116757184-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032725.4(BUD13):c.1728T>G(p.Phe576Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BUD13
NM_032725.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.498

Variant links:

Genes affected

BUD13 (HGNC:28199): (BUD13 homolog) Enables RNA binding activity. Involved in mRNA splicing, via spliceosome. Located in nucleoplasm. Part of U2-type precatalytic spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

BUD13 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BUD13	NM_032725.4 link	c.1728T>G	p.Phe576Leu	missense_variant	Exon 9 of 10	ENST00000260210.5	NP_116114.1	Q9BRD0-1
BUD13	NM_001159736.2 link	c.1326T>G	p.Phe442Leu	missense_variant	Exon 9 of 10		NP_001153208.1	Q9BRD0-2
BUD13	XM_011543035.3 link	c.1629T>G	p.Phe543Leu	missense_variant	Exon 9 of 10		XP_011541337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BUD13	ENST00000260210.5 link	c.1728T>G	p.Phe576Leu	missense_variant	Exon 9 of 10	1	NM_032725.4	ENSP00000260210.3	Q9BRD0-1
BUD13	ENST00000375445.7 link	c.1326T>G	p.Phe442Leu	missense_variant	Exon 9 of 10	1		ENSP00000364594.3	Q9BRD0-2
BUD13	ENST00000419189.1 link	n.*148T>G		non_coding_transcript_exon_variant	Exon 3 of 4	5		ENSP00000415748.1	H7C462
BUD13	ENST00000419189.1 link	n.*148T>G		3_prime_UTR_variant	Exon 3 of 4	5		ENSP00000415748.1	H7C462

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251464

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1728T>G (p.F576L) alteration is located in exon 9 (coding exon 9) of the BUD13 gene. This alteration results from a T to G substitution at nucleotide position 1728, causing the phenylalanine (F) at amino acid position 576 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.041

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.4

.;M

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;D

Vest4

0.82

MutPred

0.92

.;Gain of helix (P = 0.0496);

MVP

0.70

MPC

0.54

ClinPred

0.98

GERP RS

3.1

Varity_R

0.87

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over